The contentious debate over use of the chemical bisphenol A in plastic baby bottles and other products goes to the heart of larger questions about the use of science in regulatory decision-making, an environmental historian told a 7 April seminar at AAAS.

Sarah Vogel, program officer for the environment at the Johnson Family Foundation, said the protocols for determining whether a substance is safe remained static in the face of rapidly evolving research on the potential hazards of bisphenol A, or BPA.

The U.S. Food and Drug Administration (FDA) relied on two large industry-funded studies when it decided last year to uphold its safety standard for BPA. The standard originally was developed in the late 1970s from a single, high-dose study conducted on adult rats, Vogel said.

Such high-dose studies, standard practice in toxicology, assumed that if a chemical can cause an adverse effect, it would most likely be seen at high exposure levels. But studies during the past decade or so have suggested that BPA and other hormone-mimicking chemicals can have effects on developing animals even at very low exposure levels.

Vogel, who did her doctoral dissertation at Columbia University on the political, economic and scientific history of BPA, argues that the FDA and other federal agencies must revise the way they assess the risk of chemicals in the environment, with more emphasis on low-dose studies and the subtle reproductive and neurological effects that can result from chronic exposure to hormone-like chemicals.

The estrogenic properties of BPA have been known since the 1930s, when British medical researcher Edward Charles Dobbs identified a number of chemicals, including BPA and diethylstilbestrol, as possible synthetic estrogens. BPA was the weaker of the chemicals and was developed as an industrial chemical rather than a drug. It was used first in epoxy resins and, since the 1950s, also has been used widely in polycarbonate, a hard plastic used in beverage containers, lab and hospital equipment, compact discs, DVDs, and other products.

As the use of BPA grew—global production of the chemical now tops 6 billion pounds annually—the National Cancer Institute and the National Toxicology Program (NTP), an arm of the federal Department of Health and Human Services, conducted a study on the possible cancer-causing effects of the chemical. The carcinogenesis bioassay, completed in 1982, found "no convincing evidence of carcinogenicity" but did note that the chemical was a "reproductive toxicant" in rats.

Subsequent studies by other researchers in the late 1999s, notably Fred vom Saal and his colleagues at the University of Missouri, Columbia, began to raise more questions about the reproductive effects of BPA at levels well below the safety standard. Two industry-sponsored studies failed to replicate vom Saal's findings, but the debate was on.

The NTP, in a 2001 report on low-dose studies, found that "the current testing paradigm used for assessments of reproductive and developmental toxicity should be revisited to see if changes are needed regarding dose selection, animal model selection, age when animals are evaluated, and the end points being measured" following exposure to hormone-mimicking agents.

The U.S. Environmental Protection Agency decided in 2002, however, that it would not include low-dose considerations in its testing and screening protocols for endocrine disruptors. It called for more research, and the number of peer-reviewed studies on low-dose effects of BPA grew from just over 20 in 2000 to more than 1,000 by the time the NTP did a follow-up evaluation of the literature in 2008.

There is now extensive evidence for adverse developmental effects at low-dose exposures, Vogel said. The 2008 NTP assessment of hundreds of studies of BPA at or below the safety standard concluded there was "some concern for effects on brain, behavior and prostate gland in fetuses, infants and children at current human exposures to bisphenol A." And, it added: "The possibility that bisphenol A may alter human development cannot be dismissed."

The FDA and the European Food and Safety Authority have defended the current exposure standard for BPA (50 micrograms per kilogram of body weight) based on two large, multi-generational studies in animals, which they describe as more rigorous, sound and reliable than other studies in the literature. However, the FDA's own subcommittee of science advisers criticized the agency's 2008 draft assessment of BPA, disagreeing with the decision to rely solely on the two industry-funded toxicity studies.

"You have a tremendously huge body of research that is not looking to ask, 'What's the safe level of BPA,'" Vogel said. "It is basic research exploring a whole host of different end points, a whole host of different effects." Disagreement about the adversity of these effects lies at the heart of the debate.

Rather than looking only for standard toxic effects of BPA, Vogel said, the recent studies expose animals to extremely low levels of BPA (and other endocrine disrupting chemicals) during critical periods of development. They measure effects on developing endocrine-regulated systems. The BPA studies have found increased prostate weights, decreased sperm efficiency, increases in precancerous lesions in prostate and mammary glands, and other effects on the reproductive system. They also have found effects on brain physiology and function at levels of BPA below the federal exposure standard.

There has been a divide between those who adhere to traditional toxicological endpoints such as death, malformation, cancer, or gross changes in organ weight when evaluating the safety of BPA and those who have been studying more subtle changes at low-dose exposures, Vogel said.

"You've got people basically looking in totally different directions," she said. "And they are drawing on different ideas about what science should inform regulatory standards."

The emerging research suggests that exposure to hormone-like chemicals early in development may predispose animals to disease later in life. Whether the same is true for humans remains a matter of intense debate and study. One epidemiological study in humans, reported last year, did find an association between BPA exposure and cardiovascular disease, Vogel said. Another recent study suggests that BPA may reside in the human body longer than expected with unpredictable results, although that work has not yet been replicated.

Vogel argues that regulators need to include studies that expose developing animals to low doses of endocrine disrupting chemicals and examine a wider range of endpoints that may be related to human diseases of public health concern. "What you basically have now is a changing calculus of safety and risk," she said.

The stakes in the BPA debate continue to rise in the political arena. Legislation has been introduced in both the House and Senate to ban the use of BPA in all food and beverage containers. There also have been moves at the state and municipal level. Bills to ban or restrict BPA in children's products have been introduced in California, Maryland, Michigan and Minnesota. There also are more than 20 lawsuits pending regarding BPA, Vogel said, with potentially large liability costs if successful.

Vogel said the emphasis on BPA should not distract from a larger concern about the possible impact of combined low-level exposures to multiple chemicals of concern. Some lawmakers also are pressing for more attention to such aggregate exposures and for a fundamental reform of the Toxic Substances Control Act (TSCA) of 1976 to take such questions into account.

The final seminar in the AAAS-CHF spring series will be Tuesday 5 May, with Shobita Parthasarathy, co-director of the Science, Technology and Public Policy Program at the University of Michigan's Gerald R. Ford School of Public Policy. Her topic: "Of Micro-organisms and Men: Understanding the History and Politics of Patenting Biotechnology." The seminar will be from 4:30 to 6 p.m. in the Revelle Conference Room of the AAAS Building, 12th and H Streets, N.W., Washington, D.C.